Epithelial Mesenchymal Transition and Pancreatic Tumor Initiating CD44+EpCAM+ Cells Are Inhibited by γ-Secretase Inhibitor IX 英文参考文献.docVIP

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Epithelial Mesenchymal Transition and Pancreatic Tumor Initiating CD44+EpCAM+ Cells Are Inhibited by γ-Secretase Inhibitor IX 英文参考文献.doc

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EpithelialMesenchymalTransitionandPancreaticTumorInitiatingCD44EpCAMCellsAreInhibitedbyγ-SecretaseInhibitorIX英文参考文献

EpithelialMesenchymalTransitionandPancreaticTumor InitiatingCD44+/EpCAM+CellsAreInhibited byc-SecretaseInhibitorIX VindhyaPalagani1,MonaElKhatib1,UtaKossatz1,PrzemyslawBozko1,MartinR.Mu¨ller2, MichaelP.Manns3,TillKrech4,NisarP.Malek1,RubenR.Plentz1* 1Department of Internal Medicine I, Medical University Hospital, Tuebingen, Germany, 2Department of Internal Medicine II, Medical University Hospital, Tuebingen, Germany,3DepartmentofGastroenterology,HepatologyandEndocrinology,HannoverMedicalSchool,Hannover,Germany,4InstituteforPathology,HannoverMedical School,Hannover,Germany Abstract Pancreatic ductal adenocarcinoma (PDAC) is an aggressive disease with a high rate of metastasis. Recent studies have indicated that the Notch signalling pathway is important in PDAC initiation and maintenance, although the specific cell biologicalrolesofthepathwayremaintobeestablished.Herewesoughttoexaminethisquestioninestablishedpancreatic cancer cell lines using the c-secretase inhibitor IX (GSI IX) to inactivate Notch. Based on the known roles of Notch in developmentandstemcellbiology,wefocusedoneffectsonepithelialmesenchymaltransition(EMT)andonpancreatic tumorinitiatingCD44+/EpCAM+cells.WeanalyzedtheeffectoftheGSIIXongrowthandepithelialplasticityofhuman pancreatic cancer cell lines, and on the tumorigenicity of pancreatic tumor initiating CD44+/EpCAM+ cells. Notably, apoptosis was induced after GSI IX treatment and EMT markers were selectively targeted. Furthermore, under GSI IX treatment, decline in the growth of pancreatic tumor initiating CD44+/EpCAM+ cells was observed in vitro and in a xenograft mouse model. This study demonstrates a central role of Notch signalling pathway in pancreatic cancer pathogenesis and identifies an effective approach to inhibit selectively EMT and suppress tumorigenesis by eliminating pancreatictumorinitiatingCD44+/EpCAM+cells. Citation:PalaganiV,ElKhatibM,KossatzU,BozkoP,Mu¨llerMR,etal.(2012)EpithelialMesenchymalTransitionandPancreaticTumorInitiatingC